Abstract
Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine1,2. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI3. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and acetaminophen-induced hepatotoxicity. We demonstrate that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation and death caused by liver-toxic drugs. We identify a small-molecule inhibitor of Cx32 that protects against liver failure and death in wild-type mice when co-administered with known hepatotoxic drugs. These findings indicate that gap junction inhibition could provide a pharmaceutical strategy to limit DILI and improve drug safety.
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05 December 2013
In the version of this article initially published, Arvin Iracheta-Vellve's name was incorrectly spelled as Arvin Iracheta-Velle. The error has been corrected in the HTML and PDF versions of the article.
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Acknowledgements
The authors thank K. Willecke (University of Bonn) and D. Paul (Harvard University) for the generous gift of Cx32−/− mice, K. Willecke (University of Bonn) for connexin expressing HeLa cells, H. Duffy (Harvard Medical School) for development of the tissue scrape-and-load assay, and M. Izamis (Harvard Medical School) for high-performance liquid chromatography assistance. S.J.P. was supported in part by a Department of Defense Congressionally Directed Medical Research Program Prostate Cancer Predoctoral Training Award and a Shriners Hospitals for Children Postdoctoral Fellowship Award. The work was supported by grants from the US National Institutes of Health (DK059766 and P41 EB-002503) and from the Shriners Hospitals for Children.
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S.J.P. initiated the project, performed the experiments, analyzed data and wrote the manuscript. J.M.M. and K.R.K. performed the experiments, provided experimental advice and wrote the manuscript. S.B., M.L., A.I.-V. and A.V. performed the experiments and analyzed data. R.J. and B.P. provided conceptual and editorial support. M.L.Y. supervised the project.
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S.J.P., J.M.M., K.R.K. and M.L.Y. are inventors on a patent application, and S.J.P., K.R.K. and M.L.Y. hold founder's equity in a company pertaining to the technology described in this paper.
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Patel, S., Milwid, J., King, K. et al. Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure. Nat Biotechnol 30, 179–183 (2012). https://doi.org/10.1038/nbt.2089
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DOI: https://doi.org/10.1038/nbt.2089
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